The clinical effectiveness agency for England and Wales has finalized its decision against the drug ofatumumab for adults with chronic lymphocytic leukemia, citing high costs and inadequate evidence for its survival benefit.

The National Institute for Health and Clinical Effectiveness also announced Oct. 27 that it had terminated appraisals of two more cancer drugs: temsirolimus, for the treatment of mantle cell lymphoma, and bendamustine for the treatment of low grade non-Hodgkin’s lymphoma. In both drugs’ cases, NICE said, the manufacturer declined to supply the clinical and cost-effectiveness data NICE requires to make its decisions.

NICE also issued a final no on omalizumab, a drug licensed for severe asthma in children, despite an appeal by U.K. pediatricians.

NICE’s negative recommendation on ofatumumab (Arzerra, GlaxoSmithKline), follows draft guidance from September in which NICE had acknowledged that based on the interim results of one small, manufacturer-sponsored uncontrolled trial (n=154), ofatumumab was effective in a subgroup of people (n=59) with chronic lymphocytic leukemia in whom both fludarabine and alemtuzumab had failed. All the patients in the open-label trial received treatment with ofatumumab; in the double-refractory subgroup, 58% of patients achieved partial remission after treatment.

But NICE was not inclined to recommend the drug, citing an “absence of robust evidence from randomized controlled trials” to support ofatumumab’s efficacy; the small size of the population presented in the manufacturer’s analysis; the fact that median overall survival could not be estimated because the manufacturer had presented interim data only; and insufficient data to comparing survival with ofatumumab to survival with best supportive care.

Ofatumumab, a monoclonal antibody, received conditional marketing authorization in the United States and Europe based on the same limited clinical effectiveness data presented to NICE. Ofatumumab’s manufacturer had protested repeatedly to NICE that it could not provide data from randomized controlled trials in part because of the rarity of the disease and because there was no established treatment to serve as a comparator.

NICE concluded that although it was “likely that ofatumumab is clinically effective based on the observed [objective response rates], it was not possible to estimate the size of the clinical effect with certainty because of the absence of robust and comparative evidence and the immaturity of the data on overall survival.” NICE concluded that ofatumumab’s most plausible incremental cost-effectiveness ratio was between £60,500 and £81,500 per quality-of-life-adjusted year gained – making it too expensive “even if the robustness of the survival estimates could be improved.”

Ofatumumab, an intravenous infusion, costs £182.00 per 100 mg vial. The recommended dose is 300 mg for the first infusion, and 2000 mg for eight consecutive weekly infusions, followed four to five weeks later by four consecutive monthly infusions of 2000 mg.

NICE also said Oct. 27 that it had terminated the appraisal process for temsirolimus (Torisel, Wyeth) which has E.U. marketing authorization for the treatment of mantle cell lymphoma, after its manufacturer declined to submit evidence. The agency also said it had terminated its appraisal of bendamustine, an alkylating agent that has marketing authorization in some E.U. countries, but not the United Kingdom, to treat non-Hodgkin’s lymphoma in patients who have failed rituximab, also for lack of an evidence submission.

The agency meanwhile issued final, binding negative guidance on the use of omalizumab (Xolair, Novartis), which is recommended by NICE to treat severe uncontrolled asthma in children older than 12, for children aged 6-11.

NICE had reviewed randomized controlled trial evidence on omalizumab, which showed benefits when used in addition to inhaled corticosteroids in children younger than 12. However, the agency argued in draft guidance in August that oral corticosteroids were more the commonly used in U.K. practice and that the results could not easily apply to the U.K. population. It also complained about omalizumab’s costs.

Omalizumab injections cost between £1,665 per patient per year for 75 mgs administered every four weeks, to £26,640 per patient per year for a 600 mg dose every two weeks. Dosing is dependent on weight.

NICE estimated the incremental cost effectiveness ratio of treatment at £82,600 per QALY gained for children aged 6-11, determining it was not cost-effective for this age group.

NICE’s draft decision was met by an appeal from the Royal College of Pediatricians, which charged that NICE had wrongly applied its standard cost-effectiveness indicator, the quality-of-life-adjusted year (or QALY), to children. Further, the group charged, because the agency does recommend omalizumab in certain circumstances for children 12 and older, it was discriminating against a younger age group that is “virtually identical in immunopathology” to the older children.

The pediatricians’ appeal was rejected Oct. 25 for falling outside established grounds for an appeal.

NICE said in a press release Oct. 27 that the agency intends to “review its guidance on omalizumab for both age groups at the earliest opportunity.”

Finally Oct. 27, in accordance with draft guidance, NICE issued final guidance recommending liraglutide (Victoza, Novo Nordisk) 1.2 mg daily for people with type 2 diabetes mellitus, as part of dual or triple therapy regimens. It recommended denosumab (Prolia, Amgen) injections as a treatment option for postmenopausal women who are at increased risk of primary and secondary fractures who cannot take oral medications.

And the agency rejected, also in accordance with earlier guidance, eltrombopag (Revolade, GlaxoSmithKline) for treating chronic immune thrombocytopenic purpura in splenectomized adults who do not respond to other treatments.

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英国国家卫生与临床优化研究所(NICE)于近日做出最终决定，鉴于ofatumumab费用高昂，且支持该药存在生存率方面优势的相关证据不足，故该药物不适用于治疗成人慢性淋巴细胞性白血病。

 

NICE最终否决了对ofatumumab(Arzerra，葛兰素史克)的推荐意见并表示，鉴于该试验缺乏随机对照试验数据支持且样本量较小，加上制药商仅公布了中期数据，故目前尚无法对患者总中位生存时间进行计算，也无法就ofatumumab和最佳支持治疗的生存益处大小进行比较。

 

Ofatumumab制造商向NICE多次抗议说，目前在欧洲和美国均仅获得条件性上市许可，其无法提供该药随机对照试验数据的部分原因在于慢性淋巴细胞性白血病十分罕见，且目前也没有成熟的治疗方法可资比较。NICE表示尽管就患者对ofatumumab的客观反应率来看，该药看似具备临床疗效，但该证据未经对照试验验证显然缺乏效力，关于患者总生存率的数据目前也还不完整，故无法确切评估该药临床效力的大小。此外，应用ofatumumab的患者每获得1个质量调整寿命年(QALY)的益处，成本效益比就会相应增加60,500~81,500美元，这显然过于昂贵。

 

NICE还在新发布的用药指南中不推荐奥玛珠单抗(Xolair，诺华制药)用于年龄介于6~11岁的儿童，原因是尽管试验表明，年龄<12岁的患儿在接受皮质类固醇吸入治疗后加用奥玛珠单抗可进一步缓解病情，但在英国目前口服皮质类固醇的应用并不普遍，该疗法在英国的实施难度较大，此外，奥玛珠单抗治疗费用偏高。但指南支持将该药用于治疗年龄＞12岁且存在病情失控性重症哮喘的儿童。NICE表示将尽快就奥玛珠单抗用于不同年龄层的疗效进行评估。

 

NICE还表示，目前已终止对坦西莫斯(Torisel，惠氏，套细胞淋巴瘤治疗药)和苯达莫司汀(低恶性度霍奇金淋巴瘤治疗药)这2种癌症药物的评估，原因为这2种药物的制药商均未按照NICE要求提供药物在临床疗效和成本效益方面的数据，故不予推荐。

 

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